Molecular mechanism for a gateway drug: epigenetic changes initiated by nicotine prime gene expression by cocaine.
Molecular mechanism for a gateway drug: epigenetic changes initiated by nicotine prime gene expression by cocaine.
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DOI：
10.1126/scitranslmed.3003062
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发表时间：
2011-11-02
影响因子：
17.1
通讯作者：
Kandel ER
中科院分区：
文献类型：
--
作者：
Levine A;Huang Y;Drisaldi B;Griffin EA Jr;Pollak DD;Xu S;Yin D;Schaffran C;Kandel DB;Kandel ER
在人类中，香烟和酒精通常是入门毒品，人们首先使用大麻，可卡因或其他非法物质。为了了解药物使用的网关序列的生物学基础，我们在小鼠中开发了一种动物模型，并专注于尼古丁对可卡因后续反应的影响。我们发现，用尼古丁预处理小鼠增加了对可卡因的反应，这是通过成瘾相关行为和纹状体中的突触可塑性来评估的，纹状体是成瘾相关奖励的关键大脑区域。运动敏感性增加了98%，条件性位置偏爱增加了78%，可卡因诱导的长时程增强（LTP）减少了24%。对可卡因的反应只有在先给予尼古丁，然后同时给予尼古丁和可卡因时才会改变。颠倒给药顺序无效。可卡因对尼古丁诱导的行为和突触可塑性没有影响。尼古丁通过抑制组蛋白去乙酰化酶诱导FosB基因转录激活的能力，引起纹状体中组蛋白乙酰化，从而引发对可卡因的反应。我们用组蛋白去乙酰化酶抑制剂进一步验证了这一结论，发现它通过引发对可卡因的反应，增强FosB基因表达和LTP抑制，类似地模拟了尼古丁对可卡因的作用。相反，在Rubinstein Taybi综合征的遗传小鼠模型中，其特征是组蛋白乙酰化减少，可卡因对LTP的影响减弱。我们通过将低剂量的茶碱（一种组蛋白去乙酰化酶的激活剂）注入丘脑核，获得了类似的效果。这些来自小鼠的数据促使对流行病学数据进行分析，这表明大多数可卡因使用者在开始吸烟后开始使用可卡因，同时积极吸烟，并且在吸烟后开始使用可卡因会增加对可卡因依赖的风险，这与我们在小鼠中的数据一致。如果我们在老鼠身上的发现适用于人类，那么年轻人吸烟率的下降也可能导致可卡因成瘾的减少。
In human populations, cigarettes and alcohol generally serve as gateway drugs, which people use first before progressing to marijuana, cocaine or other illicit substances. To understand the biological basis of the gateway sequence of drug use, we developed an animal model in mice and focused on the effects of nicotine on subsequent responses to cocaine. We found that pretreatment of mice with nicotine increased the response to cocaine as assessed by both addiction-related behaviors and synaptic plasticity in the striatum, a brain region critical for addiction-related reward. Locomotor sensitization was increased by 98%, conditioned place preference was increased by 78%, and cocaine-induced reduction in long-term potentiation (LTP) was enhanced by 24%. The responses to cocaine were altered only when nicotine was administered first, and nicotine and cocaine were then administered concurrently. Reversing the order of drug administration was ineffective. Cocaine had no effect on nicotine induced behaviors and synaptic plasticity. Nicotine primed the response to cocaine by enhancing its ability to induce transcriptional activation of the FosB gene through inhibiting histone deacetylase, causing global histone acetylation in the striatum. We tested this conclusion further with a histone deacetylase inhibitor and found that it similarly simulated the actions of nicotine on cocaine by priming the response to cocaine, and enhancing FosB gene expression and LTP depression in the nucleus accumbens. Conversely, in a genetic mouse model of Rubinstein Taybi’s syndrome, characterized by reduced histone acetylation, the effects of cocaine on LTP were diminished. We achieved a similar effect pharmacologically by infusing a low-dose of theophylline, an activator of histone deacetylase, into the nucleus accumbens. These data from mice prompted an analysis of epidemiological data, which indicated that most cocaine users initiate cocaine use after the onset of smoking while actively smoking and that initiating cocaine use after smoking increases the risk of becoming dependent on cocaine, consistent with our data in mice. If our findings in mice apply to humans, a decrease in smoking rates in young people could also lead to a decrease in cocaine addiction.
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影响因子：
25
作者：
Moussawi, Khaled;Pacchioni, Alejandra;Moran, Megan;Olive, M. Foster;Gass, Justin T.;Lavin, Antonieta;Kalivas, Peter W.
通讯作者：
Kalivas, Peter W.
影响因子：
2.9
作者：
McQuown, Susan C.;Belluzzi, James D.;Leslie, Frances M.
通讯作者：
Leslie, Frances M.
影响因子：
56.9
作者：
KANDEL, D
通讯作者：
KANDEL, D
影响因子：
2.5
作者：
Salas, Ramiro;De Biasi, Mariella
通讯作者：
De Biasi, Mariella
DOI：
10.1016/j.devbrainres.2004.08.004
发表时间：
2004-11-25
期刊：
DEVELOPMENTAL BRAIN RESEARCH
影响因子：
--
作者：
Collins, SL;Montano, R;Izenwasser, S
通讯作者：
Izenwasser, S